Antibody Inducing Polyvalent Cancer Vaccines

Ragupathi, Govind; Gathuru, John; Livingston, Philip O.

doi:10.1007/0-387-27545-2_7

Cited by 38 publications

(24 citation statements)

References 74 publications

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“…Induction of antibody against weakly immunogenic tumor antigens, such as Id or Muc1, usually requires activation of T-cell help via conjugation to strong immunogens. 2,29,30 This appears also to be the case for prophylactic vaccines against polysaccharides of pathogens, such as Streptococcus pneumoniae 31,32 which may not elicit adequate T-cell help. Various vaccination strategies can therefore induce high levels of antibody, and plasma cells may persist for some time.…”

Section: Discussionmentioning

confidence: 99%

High-affinity memory B cells induced by conjugate vaccines against weak tumor antigens are vulnerable to nonconjugated antigen

Savelyeva

Shipton

Suchacki

et al. 2011

Blood

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Induction of antibody-mediated immunity against hematologic malignancies requires CD4 ؉ T-cell help, but weak tumor antigens generally fail to induce adequate T-cell responses, or to overcome tolerance. Conjugate vaccines can harness alternative help to activate responses, but memory B cells may then be exposed to leaking tumor-derived antigen without CD4 ؉ T-cell support. We showed previously using lymphoma-derived idiotypic antigen that exposure to "helpless" antigen silences the majority of memory IgG ؉ B cells. Transfer experiments now indicate that silencing is permanent. In marked contrast to IgG, most coexisting IgM ؉ memory B cells exposed to "helpless" antigen survive. Confirmation in a hapten (NP) model allowed measurement of affinity, revealing this, rather than isotype, as the determinant of survival. IntroductionTumor antigens are generally weakly immunogenic, and T-cell responses can be subject to tolerogenic pressure. 1 To avoid this, vaccines have been designed as conjugates of tumor antigens with immunogenic molecules, such as KLH. 2 Conjugation captures the large undamaged CD4 ϩ T-cell repertoire, providing T-cell help for the antitumor immune responses. 2,3 Idiotypic (Id) Ig-KLH vaccines aimed to suppress B-cell tumors via an anti-Id response are one example of the promise of this approach. [4][5][6] We have used a similar strategy to deliver Id fusion proteins via DNA vaccines. 7,8 The Id is composed of tumor-derived single chain Fv and is linked to the fragment C (FrC) of tetanus toxin. DNA vaccines encoding Id-FrC fusion proteins induce high levels of anti-Id antibody and protective immunity against B-cell lymphoma. 9 Continuous suppression of lymphoma cell growth probably requires maintenance of antibody levels. Although long-lived plasma cells can secrete antibody for extended periods, 10 memory B cells are also required. Survival factors for memory B cells are unclear, but antigen appears unnecessary. 11,12 For antibody responses induced by conjugate vaccines, the question of the effect of confronting memory B cells with free unconjugated "helpless" antigen, potentially derived from residual or emergent tumor, arises. In the case of Id antigen, or for carbohydrate antigens, this led to dramatic loss of memory B cells. 13 We found previously that the major fraction of the IgG component of the memory B-cell response induced by a DNA Id-FrC fusion vaccine was completely and specifically silenced by Id protein alone. 14 In contrast, Id protein coupled to FrC protein rescued and boosted the anti-Id IgG response, indicating the critical importance of CD4 ϩ T-cell help for maintenance of the memory B-cell response.We have now shown that silencing of the anti-Id IgG response by unconjugated antigen is permanent, but the surprising observation was that the IgM response appeared relatively unscathed. To assess the wider applicability of these findings and to investigate the effects of antigen on memory B cells at different maturational stages, we have used a model antigen, the well-defined hapten...

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Section: Discussionmentioning

confidence: 99%

High-affinity memory B cells induced by conjugate vaccines against weak tumor antigens are vulnerable to nonconjugated antigen

Savelyeva

Shipton

Suchacki

et al. 2011

Blood

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“…Advances in the chemical and enzymatic synthesis of carbohydrate and glycopeptide antigens and optimization of adjuvant use have permitted the exploration of a variety of synthetic antigen vaccines with antibody production as the end point (11 -13). Polyvalent vaccines will likely be required due to tumor cell heterogeneity, heterogeneity of the human immune response, and the correlation between overall antibody titer against tumor cells and antibody effector mechanisms (5). We showed in preclinical models that a heptavalent-KLH conjugate plus QS21 vaccine induced antibody titers comparable with those induced by monovalent vaccines containing Tn, STn, TF, MUC1, and Globo-H. Lower titers were produced against Lewis Y and GM2 (14).…”

mentioning

confidence: 84%

“…Antibodies are well suited for eradicating tumor cells from the bloodstream and eliminating early tissue invasion (4). Preclinical models have shown the clearance of circulating tumor cells and the elimination of systemic micrometastasis through the use of both passively administered and vaccine-induced antibodies (5).…”

mentioning

confidence: 99%

Pilot Study of a Heptavalent Vaccine-Keyhole Limpet Hemocyanin Conjugate plus QS21 in Patients with Epithelial Ovarian, Fallopian Tube, or Peritoneal Cancer

Sabbatini

Ragupathi

Hood

et al. 2007

Clinical Cancer Research

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132

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Purpose: To characterize the safety and immunogenicity of a heptavalent antigen-keyhole limpet hemocyanin (KLH) plus QS21 vaccine construct in patients with epithelial ovarian, fallopian tube, or peritoneal cancer in second or greater complete clinical remission. Experimental Design: Eleven patients in this pilot trial received a heptavalent vaccine s.c. containing GM2 (10 μg), Globo-H (10 μg), Lewis Y (10 μg), Tn(c) (3 μg), STn(c) (3 μg), TF(c) (3 μg), and Tn-MUC1 (3 μg) individually conjugated to KLH and mixed with adjuvant QS21(100 μg). Vaccinations were administered at weeks 1, 2, 3, 7, and 15. Periodic blood and urine samples were obtained to monitor safety (complete blood count, comprehensive panel, amylase, thyroid-stimulating hormone, and urinalysis) and antibody production (ELISA, fluorescence-activated cell sorting, and complement-dependent cytotoxicity). Results: Eleven patients were included in the safety analysis; 9 of 11 patients remained on study for at least 2 weeks past fourth vaccination and were included in the immunologic analysis (two withdrew, disease progression). The vaccine was well tolerated. Self-limited and mild fatigue (maximum grade 2 in two patients), fever, myalgia, and localized injection site reactions were most frequent. No clinically relevant hematologic abnormalities were noted. No clinical or laboratory evidence of autoimmunity was seen. Serologic responses by ELISA were largely IgM against each antigen with the exception of Tn-MUC1 where both IgM and IgG responses were induced. Antibody responses were generally undetectable before immunization. After immunization, median IgM titers were as follows: Tn-MUC1, 1:640 (IgG 1:80); Tn, 1:160; TF, 1:640; Globo-H, 1:40; and STn, 1:80. Only one response was seen against Lewis Y; two were against GM2. Eight of nine patients developed responses against at least three antigens. Antibody titers peaked at weeks 4 to 8 in all patients. Fluorescence-activated cell sorting and complement-dependent cytotoxicity analysis showed substantially increased reactivity against MCF7 cells in seven of nine patients, with some increase seen in all patients. Conclusions: This heptavalent-KLH conjugate plus QS21 vaccine safely induced antibody responses against five of seven antigens. Investigation in an adequately powered efficacy trial is warranted.

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“…For example, immunization against Aβ might be helpful at reducing α-syn and tau if administered at early disease stages [62]; likewise, α-syn antibodies might also be helpful in AD [162], and immunization against tau might be useful for PD [161,163]. In this sense, identifying and targeting polyvalent antigens or using single-chain polyvalent antibodies targeting simultaneously Aβ, tau, and α-syn could have synergistic effects, as it occurs with polyvalent vaccines for certain cancers and infections [164,165]. In the case of AD, targeting both Aβ and tau at the same time might improve the outcome of immunotherapeutic clinical trials, as it is likely that both proteins synergistically contribute to the progression of the pathology.…”

Section: Developing New Technologies For Immunotherapymentioning

confidence: 99%

Immunotherapeutic Approaches Targeting Amyloid-β, α-Synuclein, and Tau for the Treatment of Neurodegenerative Disorders

2016

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Disease-modifying alternatives are sorely needed for the treatment of neurodegenerative disorders, a group of diseases that afflict approximately 50 million Americans annually. Immunotherapy is one of the most developed approaches in this direction. Vaccination against amyloid-β, α-synuclein, or tau has been extensively explored, specially as the discovery that these proteins may propagate cell-to-cell and be accessible to antibodies when embedded into the plasma membrane or in the extracellular space. Likewise, the use of passive immunization approaches with specific antibodies against abnormal conformations of these proteins has also yielded promising results. The clinical development of immunotherapies for Alzheimer's disease, Parkinson's disease, frontotemporal dementia, dementia with Lewy bodies, and other neurodegenerative disorders is a field in constant evolution. Results to date suggest that immunotherapy is a promising therapeutic approach for neurodegenerative diseases that progress with the accumulation and prion-like propagation of toxic protein aggregates. Here we provide an overview of the most novel and relevant immunotherapeutic advances targeting amyloid-β in Alzheimer's disease, α-synuclein in Alzheimer's disease and Parkinson's disease, and tau in Alzheimer's disease and frontotemporal dementia.

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Antibody Inducing Polyvalent Cancer Vaccines

Cited by 38 publications

References 74 publications

High-affinity memory B cells induced by conjugate vaccines against weak tumor antigens are vulnerable to nonconjugated antigen

High-affinity memory B cells induced by conjugate vaccines against weak tumor antigens are vulnerable to nonconjugated antigen

Pilot Study of a Heptavalent Vaccine-Keyhole Limpet Hemocyanin Conjugate plus QS21 in Patients with Epithelial Ovarian, Fallopian Tube, or Peritoneal Cancer

Immunotherapeutic Approaches Targeting Amyloid-β, α-Synuclein, and Tau for the Treatment of Neurodegenerative Disorders

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